Thiol and disulfide-containing agents for increasing meibomian gland lipid secretion

ABSTRACT

Described herein are compositions and methods for the increasing the quantity of lipids secreted from meibomian glands. Such compositions and methods are useful for the treatment of meibomian gland dysfunction and disorders resulting therefrom.

CROSS REFERENCE

This application is a continuation of U.S. patent application Ser. No.16/795,497, filed on Feb. 19, 2020, which is a continuation of U.S.patent application Ser. No. 15/279,301, filed on Sep. 28, 2016, nowissued as U.S. Pat. No. 10,688,122 on Jun. 23, 2020, and claims thebenefit of U.S. Provisional Application No. 62/233,906, filed Sep. 28,2015, and U.S. Provisional Application No. 62/233,941, filed Sep. 28,2015, all of which are incorporated by reference herein in theirentirety.

BACKGROUND OF THE INVENTION

Meibomian glands are glands arranged vertically within the eyelid nearthe lashes. The force of an eyelid blink causes oil to be excreted ontothe posterior lid margin. The oil is the “staying power” of the tearsthat helps prevent rapid tear evaporation. In a patient with Meibomiangland dysfunction (MGD), vision is affected because there is too much ortoo little oil in the tear film.

The meibomian glands are large sebaceous glands located in the eyelids,and unlike skin, are unassociated with hair. The meibomian glandsproduce the lipid layer of the tear film that protects it againstevaporation of the aqueous phase. The meibomian gland orifice is locatedon the epithelial side of the lid margin, and is only a few hundredmicrons from the mucosal side. The glands are located on both upper andlower eyelids, with higher amounts of the glands on the upper eyelid. Asingle meibomian gland is composed of clusters of secretory acini thatare arranged circularly around a long central duct and connected to itby short ductules. The terminal part of the central duct is lined by aningrowth of the epidermis that covers the free lid margin and forms ashort excretory duct that opens as an orifice at the posterior part ofthe lid margin just anterior to the mucocutaneous junction near theinner lid border. The oily secretion composed of lipids is synthesizedwithin the secretory acini. The lipid secretion is a liquid at near bodytemperature and is delivered to the skin of the lid margin as a clearfluid, called “meibum.” It forms shallow reservoirs on the upper andlower lid margins, and consists of a complex mixture of cholesterol,wax, cholesteryl esters, phospholipids, with small amounts oftriglycerides, triacylglycerols, and hydrocarbons. The separatemeibomian glands are arranged in parallel, and in a single rowthroughout the length of the tarsal plates in the upper and lower lids.The extent of the glands corresponds roughly to the dimensions of thetarsal plates.

The eyelid margin is the source of physiologically important lipidsecretion, meibum. The eyelid meibomian gland secretions form the outerlayer of the tear film. Functions which have been attributed to thistear film lipid layer are: (1) a lubricant facilitating the movement ofthe eyelids during a blink, (2) a barrier preventing evaporation of theaqueous tear fluid, and (3) a barrier to the entry of microorganisms andorganic matter such as pollen.

The moving eyelids spread meibum across the ocular surface and mix itwith aqueous tears (AT), which are produced by lacrimal glands. Mixingand spreading of meibum and AT result in a near-continuous structurecalled tear film (TF), which covers the entire ocular surface and servesmultiple purposes, including protective, lubricatory, nutritional, andantimicrobial, among others. TF was also linked to visual acuity becauseit provides a smoother ocular surface which improves the opticalproperties of the eye. However, TF is not homogeneous, which is notsurprising considering that lipids do not easily form aqueous solutionsand tend to separate by forming a clearly hydrophobic lipid-enrichedsub-phase. A classical view on the TF structure presumes a three-layerorganization of TF. As lipids are, typically, less dense than water,they accumulate on the surface of the aqueous sub-phase thus forming alipid-enriched outer-most layer of TF (also called tear film lipidlayer, or TFLL). Beneath the TFLL is a much more hydrophilic aqueouslayer enriched with water-soluble proteins, carbohydrates, salts, andother more or less hydrophilic compounds. The closest to the cornealepithelium is believed to be a relatively hydrophilic mucin-enrichedglycocalyx layer, which is formed primarily of membrane-bound mucins. Byusing interferometry, the depth of TFLL was estimated to be ˜40-90nanometers, while the aqueous layer was found to be much thicker atabout 4 micrometers. It is important to realize that all three layersare soft and dynamic structures, where changes occur as a result ofnumerous simultaneously manifesting factors, e.g. mechanical movementsof the eyelids, continuous secretion of meibum, aqueous tears andmucins, and AT evaporation and drainage through nasal ducts. If the eyeis forced to stay open without blinking, the human TF quicklydeteriorates, thins, and breaks—a phenomenon known as tear break-up.

The tear break-up time (TBUT) for humans is measured in seconds. It haslong been considered an important and objective diagnostic parameter inevaluating the health of the ocular surface. TBUT is widely used inophthalmic practice to diagnose dry eye—a multifactorial condition (ordisease) whose onset and progress is linked to the deterioration of TFin general, and TFLL in particular. When the break-up occurs, the corneabecomes exposed to air, causing a discomfort to the patient. Theincomplete coverage of the ocular surface with TF also increases thechances of damage to the corneal epithelium cells because of excessivedehydration, abrasions, irritation, inflammation, infections, etc.Another cause of the TF instability are meibomian glands incapable ofsecreting enough meibum of the necessary quality, e.g. because of MGDassociated with meibomian gland inflammation and/or obstruction.

Lipids produced by the meibomian glands are the main component of thesuperficial lipid layer of the tear film that protects it againstevaporation of the aqueous phase and is believed also to stabilize thetear film by lowering surface tension. Alterations of the lipid phasemore frequently point to MGD than alterations in isolated aqueous phase,as reported in a study by Heiligenhaus et al. (Heiligenhaus et al.,Therapie. von Benetzungsstorungen. Klin. Monatsbl. Augenheilkd., 1994,Vol. 204, pages 162-168) where it was observed that a lipid deficiencyoccurred in 76.7% of dry eye patients compared with only 11.1% of thosewith isolated alterations of the aqueous phase. Hence, meibum lipids areessential for the maintenance of ocular surface health and integrity.

Lipids are the major components of meibum (also known as “meibomiangland secretions”). The biochemical composition of meibum is extremelycomplex and very different from that of sebum. Lipids are universallyrecognized as major components of human and animal meibum. In humans,more than 90 different proteins have been identified in meibomian glandsecretions. A large number of investigators have attempted tocharacterize the meibum, and there has been a large range of amounts oflipids recovered by investigators (Table 1), the likely cause being theuse of different collection and analysis techniques.

TABLE 1 Type and Amount of Each Lipid Present in the Meibum. LipidPolarity Amount Free Fatty Acids Non-Polar  0.0-10.4% Wax EstersNon-Polar 28.0-68.0% Cholesterol Esters Non-Polar  0.0-39.0% DiestersNon-Polar  2.3-17.6% Free sterols Non-Polar Trace-30.0%  MonoglyceridesNon-Polar Trace-2.6% Diglycerides Non-Polar Trace-3.3% TriglyceridesNon-Polar Trace-9.0% Fatty Acid Amides Non-Polar Unknown HydrocarbonsNon-Polar Trace-7.5% Phospholipids Polar  0.0-14.8% Sphingolipids PolarUnknown ω-Hydroxy Fatty Acids Polar Unknown

In subjects without MGD, the meibum lipid is a pool of clear oil. InMGD, the quantity, quality and composition of the secreted material isaltered. Thus, MGD is characterized by lipid deficiency. Further, inMGD, the quality of expressed lipid varies in appearance from a clearfluid, to a viscous fluid containing particulate matter and denselyopaque, toothpaste-like material. The meibomian orifices may exhibitelevations above surface level of the lid, which is referred to asplugging or pouting, and is due to obstruction of the terminal ducts andextrusion of a meibum lipids of increased viscosity.

Lipid deficiency and increased viscosity of meibum are importantpathogenic factors in MGD and are observed in majority of cases ofobstructive MGD. Therefore it is highly desired to enhance lipogenesisand lipid secretion from the meibomian gland, to overcome lipiddeficiency as well as reduce the viscosity of meibum oil compositionwhich allows for dissolution of any obstruction of the meibomian gland.

Highly viscous meibum is mixed with hyperkeratotic cell material, asseen in expressed pathologic human meibum prepared as smears or inimpression cytology and in histopathology, as verified by molecularbiology and immunohistochemistry. Increased viscosity has also beenobserved inside the obstructed glands of animal models. It is thereforedesirable to soften and liquefy the obstructing lipids in order to openthe duct and restore normal flow of excreted lipids.

Meibomian gland dysfunction, or MGD, is a leading contributor of dry eyesyndrome, and is often characterized by insufficient lipid delivery, bythe meibomian gland, to the surface of the eye. MGD, also termedposterior blepharitis, is the most common form of lid margin disease. Inthe early stages, patients are often asymptomatic, but if leftunmanaged, MGD can cause or exacerbate dry eye symptoms and eyelidinflammation. The oil glands become blocked with thickened secretions.Chronically clogged glands eventually become unable to secrete oil whichresults in permanent changes in the tear film and dry eyes. Symptoms ofMGD include eye dryness, burning sensation, itching, stickiness,watering, sensitivity to light, red eyes, and blurred vision.

MGD is a leading contributor of dry eye syndrome. The occurrence of dryeye syndrome is widespread and affects about 20 million patients in theUnited States alone. Dry eye syndrome is a disorder of the ocularsurface resulting from either inadequate tear production or excessiveevaporation of moisture from the surface of the eye. Tears are importantto corneal health because the cornea does not contain blood vessels, andrelies on tears to supply oxygen and nutrients. Tears and the tear filmare composed of lipids, water, and mucus, and disruption of any of thesecan cause dry eye. MGD is not synonymous with posterior blepharitis,which describes inflammatory conditions of the posterior lid margin. MGDmay cause posterior blepharitis, but MGD may not always be associatedwith inflammation or posterior blepharitis. Clinical signs of MGDinclude meibomian gland dropout, altered meibomian gland secretion, andchanges in lid morphology.

Obstructive MGD is characterized by all or some of the following: 1)chronic ocular discomfort, 2) anatomic abnormalities around themeibomian gland orifice (which is one or more of the following: vascularengorgement, anterior or posterior displacement of the mucocutaneousjunction, irregularity of the lid margin) and 3) obstruction orqualitative or quantitative changes in the glandular secretion(decreased meibum expression by moderate digital pressure).

Currently, standard treatment to MGD is somewhat limited to heating thelids to increase oil production and melt the oil that has solidified inthe glands by warm compresses, applying light pressure to the lid marginnear the lash line, and manually removing the thickened secretions aswell as pharmacological treatments like antibiotics andanti-inflammatory agents. However, these treatments may be frustratingto patients and ophthalmologists. Massage of the eyelid provides onlypartial and temporary relief of obstruction of the meibomian glands andthis could be painful. Conventional approaches for warm compresses applyheat to the outer surface of the eyelid; therefore the heat isfrequently of limited effectiveness. The use of topical antibiotics andcorticosteroids to suppress the bacterial colonization and inflammationof the eyelid margin associated with MGD has been shown to be effectivein the relief of symptoms and the signs of MGD, however, the success ofthis treatment may have nothing to do with the changed meibum.Antibiotics, particularly the tetracyclines (including doxycycline,tetracycline, and minocycline) and azithromycin are used to suppressbacterial colonization and reduce inflammation of the lid margin;however, drug intolerance and prolonged therapy have limited theclinical application of oral antibiotics.

Lid hygiene is considered the primary treatment for MGD and consists ofthree components: 1) application of heat, 2) mechanical massage ofeyelids and 3) cleansing the eyelid. Eyelid warming procedures improvemeibomian gland secretion by melting the pathologically alteredmeibomian lipids. Warming is achieved by warm compresses or devices.Mechanical lid hygiene includes the use of scrubs, mechanical expressionand cleansing with various solutions of the eyelashes and lid margins.Lid margins are optionally also cleansed with hypoallergenic bar soap,dilute infant shampoo or commercial lid scrubs. Physical expression ofmeibomian glands is performed in a physician's office or is performed bythe patient at home. The technique varies from gentle massage of thelids against the eyeball to forceful squeezing of the lids eitheragainst each other or between a rigid object on the inner lid surfaceand a finger, thumb, or rigid object (such as a glass rod, Q-tip, ormetal paddle) on the outer lid surface. The rigid object on the innerlid surface protects the eyeball from forces transferred through theeyelid during expression and to offer a stable resistance, to increasethe amount of force that is applied to the glands.

Eyelid warming is limited because the warming melts the lipids, but doesnot address movement of the keratinized material. Further, eyelidwarming induces transient visual degradation due to corneal distortion.Mechanical lid hygiene is also limited because the force needed toremove an obstruction can be significant, resulting in significant painto the patient. The effectiveness of mechanical lid hygiene is limitedby the patient's ability to tolerate the associated pain during theprocedure. Other treatments for MGD are limited.

Physical opening of meibomian glands obstruction by meibomian glandexpression is an acceptable method to improve meibomian gland secretionand dry eye symptoms. In addition probing of the meibomian gland canalhas been used to open the obstructed canal. Both methods, expression andprobing, are limited, however, by the pain induced by the procedure, thepossible physical insult to the gland and canal structures and theirshort lived effect estimated at days and weeks.

In summary, each of these treatments has a different shortcoming and thetreatment of MGD remains challenging. Therefore, methods are needed toimprove patient comfort, which will not cause harm to the meibomianglands and canals, that will reduce the dependency on frequent officevisits and improve secretion of meibum.

Emerging treatments for MGD include the use of mucolytic and/orkeratolytic agents. The goal of mucolytic therapy is to facilitatephysiological clearance by optimizing the viscoelasticity of mucus,while keratolytic therapy aims to soften keratin, a major component ofthe skin.

Acetylcysteine, also known as N-acetylcysteine or N-acetyl-L-cysteine(abbreviated NAC), is a pharmaceutical drug and nutritional supplementused primarily as a mucolytic agent. Acetylcysteine is an acetylatedderivative of L-cysteine where an acetyl group is attached to thenitrogen atom, known to have mucolytic, anti-collagenolytic, andanti-oxidant properties. It is used as a cough medicine since it breaksdisulfide bonds in mucus and liquefies it, making it easier to cough up.It is also this action of breaking disulfide bonds that makes it usefulin thinning the abnormally thick mucus in cystic and pulmonary fibrosispatients. Akyol-Salman et al., (J. Ocul. Pharmacol. Ther., 2010, Vol.26(4), pages 329-33) evaluated the efficacy of topical N-acetyl-cysteine(NAC) therapy in patients with meibomian gland dysfunction (MGD). Qiaoand Yan (Clinical Ophthalmology 2013, Vol. 7, pages 1797-1803) reviewedseveral emerging treatment options for MGD, including NAC.

Despite the possible treatment options for MGD, it is still difficult toobtain complete relief of signs and symptoms.

SUMMARY OF THE INVENTION

The present invention provides methods for enhancing lipogenesis and/orlipid secretion from the meibomian glands to the eyelid. Without wishingto be bound by any theory or mechanism, it is speculated that enhancedlubrication of the eyelid margin by natural lipids which are the majorconstituents of the meibum would ameliorate MGD and/or related symptoms.

The present invention is based on the unexpected discovery that includethiol-containing, —SeH containing, and/or disulfide-containing drugs arecapable to increase the production of lipids in meibomian glands and/orincrease the secretion of lipids from meibomian glands to the eyelid.This capability may be effective in preventing, treating and/orameliorating certain adverse eyelid conditions, such as MGD.

The present invention provides, in an aspect, a method for increasinglipid secretion from a meibomian gland, comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition comprising an ophthalmically-acceptable carrierand a therapeutically-effective amount of at least one agent whichincreases lipogenesis in the meibomian gland or increases lipidsecretion from the meibomian gland, wherein the agent comprises asulfhydryl group or a disulfide.

The present invention further provides, in another aspect, a method fortreating meibomian gland dysfunction (MGD), comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition comprising an ophthalmically-acceptable carrierand a therapeutically-effective amount of at least one agent, whereinthe agent is selected from the group consisting of captopril,Zofenopril, Tiopronin, Penicillamine, Gluthatione, Dithiothreitol,Thiorphan, Cysteamine, Bucillamine, Dimercaprol, 1,1-Ethanedithiol,Dimercaptosuccinic acid, Furan-2-ylmethanethiol, Omapatrilat, OvothiolA, Pantetheine, Rentiapril, Thiosalicylic acid, Tixocortol, Mycothiol,Coenzyme A, and Coenzyme B, or wherein the agent comprises a disulfide.

The present invention further provides, in another aspect, a method forlowering the melting point of lipids secreted from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and a therapeutically-effective amountof at least one agent which increases lipogenesis in the meibomian glandor increases lipid secretion from the meibomian gland, wherein the agentcomprises a sulfhydryl group or a disulfide

The present invention further provides, in another aspect, a method forreducing the viscosity of lipids secreted from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and a therapeutically-effective amountof at least one agent which increases lipogenesis in the meibomian glandor increases lipid secretion from the meibomian gland, wherein the agentcomprises a sulfhydryl group or a disulfide

In certain embodiments, the agent comprises thiol group. In certainembodiments, the agent is selected from the group consisting ofCaptopril, Zofenopril, Tiopronin, Penicillamine, L-Cysteine,Selenocysteine, Gluthatione, Dithiothreitol, Thiorphan, Cysteamine,Bucillamine, Dimercaprol, 1,1-Ethanedithiol, Dimercaptosuccinic acid,Furan-2-ylmethanethiol, Omapatrilat, Ovothiol A, Pantetheine,Rentiapril, Thiosalicylic acid, Tixocortol, Mycothiol, Coenzyme A, andCoenzyme B. In certain embodiments, the agent is selected from the groupconsisting of Captopril, Zofenopril, Tiopronin, Penicillamine,Gluthatione, Dithiothreitol, Thiorphan, Cysteamine, Bucillamine,Dimercaprol, 1,1-Ethanedithiol, Dimercaptosuccinic acid,Furan-2-ylmethanethiol, Omapatrilat, Ovothiol A, Pantetheine,Rentiapril, Thiosalicylic acid, Tixocortol, Mycothiol, Coenzyme A, andCoenzyme B. Each possibility represents a separate embodiment of theinvention.

In certain embodiments, the agent comprises a disulfide bond. In certainembodiments, the agent is selected from the group consisting ofdisulfiram, Psammaplin A, Dixanthogen, Pantethine, Fursultiamine,Octotiamine, Sulbutiamine, Prosultiamine, Thiram, Lipoic acid,Lenthionine, Ajoene, Allicin, Gemopatrilat, and Sulfanegen. Eachpossibility represents a separate embodiment of the invention.

In certain embodiments, the ophthalmically-acceptable carrier comprisesat least one ophthalmically-acceptable excipient.

In certain embodiments, the methods described above further comprise thestep of administering to the patient a keratolytic agent. In certainembodiments, the keratolytic agent is selected from the group consistingof benzoyl peroxide, coal tar, dithranol, salicylic acid, seleniumdisulfide, alpha-hydroxy acid, urea, boric acid, retinoic acid, lacticacid, sodium thioglycolate or allantoin.

In certain embodiments, the meibomian gland dysfunction is characterizedby obstruction of a meibomian gland. In certain embodiments, the topicaladministration of the agent to the eyelid margin of the patient isrepeated until the meibomian gland obstruction is substantially removed.In certain embodiments, the topical administration of the agent to theeyelid margin of the patient is periodically repeated to preventformation of a meibomian gland obstruction.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent application file contains at least one drawing executed incolor. Copies of this patent application with color drawings will beprovided by the Office upon request and payment of the necessary fee. Anunderstanding of the features and advantages of the present disclosurewill be obtained by reference to the following detailed description thatsets forth illustrative embodiments, in which the principles of thedisclosure are utilized, and the accompanying drawings of which:

FIG. 1 is an illustration of Oil-red-0 staining in 3D Sebocytesepithelium for the control.

FIG. 2 is an illustration of Oil-red-0 staining in 3D Sebocytesepithelium for 1.0 micromolar 12-mercaptododecanoic acid.

FIG. 3 is an illustration of Oil-red-0 staining in 3D Sebocytesepithelium for 0.1 micromolar 12-mercaptododecanoic acid.

FIG. 4 provides illustrative synthetic methods to prepare the thiol anddisulfide-containing lipids employed in the methods described herein.

FIG. 5 provides illustrative synthetic methods to prepare the thiol anddisulfide-containing lipids employed in the methods described herein.

FIG. 6 provides illustrative synthetic methods to prepare the thiol anddisulfide-containing lipids employed in the methods described herein.

FIG. 7 provides illustrative synthetic methods to prepare the thiol anddisulfide-containing lipids employed in the methods described herein.

FIG. 8 provides illustrative synthetic methods to prepare the thiol anddisulfide-containing lipids employed in the methods described herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides, for the first time, non-hormonal agentsuseful for enhancing secretion of the meibum lipids in vivo.

More specifically, described herein are methods for enhancinglipogenesis and/or lipid secretion by administering a thiol-containing,—SeH containing, or disulfide-containing agent which increases theproduction of lipids in meibomian glands, increases the quantity oflipids secreted from meibomian glands, and/or alters the composition oflipids secreted from meibomian glands. The agents described hereininclude agents for acute therapies, for use, e.g., by a physician orother trained specialist, and agents for chronic therapies, e.g., eitherby a physician or other trained specialist, or by the patient. Certainlipogenesis and lipid secretion enhancing agents are described herein;further provided herein are methods for preparing a compositioncomprising lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing agents as well as their use inmethods of treatment of patients.

The terms “meibomian gland dysfunction” and “MGD” as interchangeablyused herein, refer to chronic, diffuse abnormality of the meibomianglands, that is characterized by terminal duct obstruction orqualitative or quantitative changes in the glandular secretion, or both.MGD may result in alteration of the tear film viscosity, eye irritationsymptoms, inflammation, or ocular surface disease. The most prominentaspects of MGD are obstruction of the meibomian gland orifices andterminal ducts and changes in the meibomian gland secretions. MGD alsorefers to functional abnormalities of the meibomian gland, while“meibomian gland disease,” describes a broad range of meibomian glanddisorders, that includes neoplasia and congenital disease.

According to the principles of the present invention, thiol-containing,—SeH containing, or disulfide-containing drugs or agents which inducelipogenesis and meibum lipid secretion, can be used, e.g., as treatmentfor MGD through thiol-mediated lipid over-secretion mechanisms. Moreaccording to the principles of the present invention, disulfidecontaining drugs, like disulfiram, present thiol or sulfhydryl radicalsonce the disulfide bond is cleaved within the body by enzymes orchemical reactions.

Drug-induced activation of cellular lipogenesis thus represents a newapproach for therapeutic treatment of meibomian gland dysfunctionthrough enhanced synthesis of cholesterol and increased production offatty acids and triglycerides that lead to alterations in composition ofthe meibum lipids, by decreasing the melting point and viscosity of themeibum lipids, which results in a more fluid appearance of meibumlipids.

The lipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing agents described herein are usefuleither as an acute therapy (e.g., by a trained specialist or physician)or as a chronic therapy (e.g., in the hands of a patient, oralternatively, by a trained specialist or physician). The agents aretested, in certain embodiments, using the assays and methods describedherein (e.g., as described in the examples).

Drugs that have thiol groups, or sulfhydryl radicals have previouslybeen reported to cause sebum over-production. Drugs containing thiolgroups or sulfhydryl radicals were also reported to cause Pemphigus, askin disease resembling seborrheic dermatitis, characterized by oilyskin. Xanthine oxidoreductase (XOR) is an essential enzyme for milklipid droplet secretion and it is known to exist in two distinct andinterconvertible enzymatic forms, a thiol reduced form (XD) and a thioloxidized form (XO), which differ in their enzymatic properties andconformations. Mammary tissue and milk fat globule membranes (MFGM) havebeen shown to contain a thiol oxidase that is capable of converting XDto XO. The association between XOR and the apical plasma membrane ismediated by thiol-dependent processes that involve the formation ofdisulphide bond cross-links with Butyrophilin protein (the most abundantprotein in MFGM also essential for secretion of lipid droplets inmammary gland), ADPH or other membrane proteins, and/or conformationalchanges in XOR. The levels of expression and the apical membranelocalization of XOR are crucial properties of secreting mammaryepithelial cells and the membrane association of XOR regulates couplingof cytoplasmic lipid droplets to the apical plasma membrane during lipidsecretion.

The present invention provides, in an aspect, a method for increasinglipid secretion from a meibomian gland, comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition comprising an ophthalmically-acceptable carrierand a therapeutically-effective amount of at least one agent whichincreases lipogenesis in the meibomian gland or increases lipidsecretion from the meibomian gland, wherein the agent comprises asulfhydryl group, —SeH group, or a disulfide.

The present invention provides, in an aspect, a method for increasinglipid secretion from a meibomian gland, comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition comprising an ophthalmically-acceptable carrierand a therapeutically-effective amount of an agent which increaseslipogenesis in the meibomian gland or increases lipid secretion from themeibomian gland, wherein the agent comprises a sulfhydryl group, —SeHgroup, or a disulfide.

The present invention provides, in an aspect, a method for increasinglipid secretion from a meibomian gland, comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition consisting of an ophthalmically-acceptablecarrier and a therapeutically-effective amount of an agent whichincreases lipogenesis in the meibomian gland or increases lipidsecretion from the meibomian gland, wherein the agent comprises asulfhydryl group, —SeH group, or a disulfide.

The present invention provides, in an aspect, a method for increasinglipid secretion from a meibomian gland, comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition consisting of an ophthalmically-acceptablecarrier and a therapeutically-effective amount of an agent whichincreases lipogenesis in the meibomian gland or increases lipidsecretion from the meibomian gland, wherein the agent comprises asulfhydryl group, —SeH group, or a disulfide, and wherein theophthalmically-acceptable carrier comprises at least oneophthalmically-acceptable excipient.

The present invention provides, in an aspect, a method for increasinglipid secretion from a meibomian gland, comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition consisting of an ophthalmically-acceptablecarrier and a therapeutically-effective amount of an agent whichincreases lipogenesis in the meibomian gland or increases lipidsecretion from the meibomian gland, wherein the agent comprises asulfhydryl group, —SeH group, or a disulfide, and wherein theophthalmically-acceptable carrier comprises no more than twoophthalmically-acceptable excipients.

The present invention provides, in an aspect, a method for increasinglipid secretion from a meibomian gland, comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition consisting of an ophthalmically-acceptablecarrier and a therapeutically-effective amount of an agent whichincreases lipogenesis in the meibomian gland or increases lipidsecretion from the meibomian gland, wherein the agent comprises asulfhydryl group, —SeH group, or a disulfide, and wherein theophthalmically-acceptable carrier comprises no more than threeophthalmically-acceptable excipients.

The present invention provides, in an aspect, a method for increasinglipid secretion from a meibomian gland, comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition consisting of an ophthalmically-acceptablecarrier and a therapeutically-effective amount of an agent whichincreases lipogenesis in the meibomian gland or increases lipidsecretion from the meibomian gland, wherein the agent comprises asulfhydryl group, —SeH group, or a disulfide, and wherein theophthalmically-acceptable carrier comprises no more than fourophthalmically-acceptable excipients.

The present invention further provides, in another aspect, a method fortreating meibomian gland dysfunction (MGD), comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition comprising an ophthalmically-acceptable carrierand a therapeutically-effective amount of at least one agent, whereinthe agent is selected from the group consisting of Captopril,Zofenopril, Tiopronin, Penicillamine, Gluthatione, Dithiothreitol,Thiorphan, Cysteamine, Bucillamine, Dimercaprol, 1,1-Ethanedithiol,Dimercaptosuccinic acid, Furan-2-ylmethanethiol, Omapatrilat, OvothiolA, Pantetheine, Rentiapril, Thiosalicylic acid, Tixocortol, Mycothiol,Coenzyme A, and Coenzyme B, or wherein the agent comprises a disulfide.

The present invention further provides, in another aspect, a method forlowering the melting point of lipids secreted from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and a therapeutically-effective amountof at least one agent which increases lipogenesis in the meibomian glandor increases lipid secretion from the meibomian gland, wherein the agentcomprises a sulfhydryl group, —SeH group, or a disulfide

The present invention further provides, in another aspect, a method forreducing the viscosity of lipids secreted from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and a therapeutically-effective amountof at least one agent which increases lipogenesis in the meibomian glandor increases lipid secretion from the meibomian gland, wherein the agentcomprises a sulfhydryl group, —SeH group, or a disulfide

In certain embodiments, the agent comprises thiol group, or —SeH group.In certain embodiments, the agent is selected from the group consistingof Captopril, Zofenopril, Tiopronin, Penicillamine, L-Cysteine,Selenocysteine, Gluthatione, Dithiothreitol, Thiorphan, Cysteamine,Bucillamine, Dimercaprol, 1,1-Ethanedithiol, Dimercaptosuccinic acid,Furan-2-ylmethanethiol, Omapatrilat, Ovothiol A, Pantetheine,Rentiapril, Thiosalicylic acid, Tixocortol, Mycothiol, Coenzyme A, andCoenzyme B. In certain embodiments, the agent is selected from the groupconsisting of Captopril, Zofenopril, Tiopronin, Penicillamine,Gluthatione, Dithiothreitol, Thiorphan, Cysteamine, Bucillamine,Dimercaprol, 1,1-Ethanedithiol, Dimercaptosuccinic acid,Furan-2-ylmethanethiol, Omapatrilat, Ovothiol A, Pantetheine,Rentiapril, Thiosalicylic acid, Tixocortol, Mycothiol, Coenzyme A, andCoenzyme B. Each possibility represents a separate embodiment of theinvention.

In certain embodiments, the agent is a —SH or —SeH containing aminoacid, peptide, or peptidomimetic. In certain embodiments, the —SH or—SeH containing amino acid, peptide, or peptidomimetic is selected fromthe group consisting of Captopril, Zofenopril, Tiopronin, Penicillamine,L-Cysteine, Selenocysteine, Gluthatione, Thiorphan, Bucillamine,Omapatrilat, Pantetheine, or Mycothiol.

In certain embodiments, the agent is a —SH or —SeH containing aryl orheteroaryl compound. In certain embodiments, the —SH or —SeH containingaryl or heteroaryl compound is selected from the group consisting ofFuran-2-ylmethanethiol, Ovothiol A, Rentiapril, or Thiosalicylic acid.

In certain embodiments, the agent comprises a disulfide bond. In certainembodiments, the agent is selected from the group consisting ofdisulfiram, Psammaplin A, Dixanthogen, Pantethine, Fursultiamine,Octotiamine, Sulbutiamine, Prosultiamine, Thiram, Lipoic acid,Lenthionine, Ajoene, Allicin, Gemopatrilat, and Sulfanegen. Eachpossibility represents a separate embodiment of the invention.

In certain embodiments, the ophthalmically-acceptable carrier comprisesat least one ophthalmically-acceptable excipient.

In certain embodiments, the methods described above further comprise thestep of administering to the patient a keratolytic agent. In certainembodiments, the keratolytic agent is selected from the group consistingof benzoyl peroxide, coal tar, dithranol, salicylic acid, seleniumdisulfide, alpha-hydroxy acid, urea, boric acid, retinoic acid, lacticacid, sodium thioglycolate or allantoin.

In certain embodiments, the meibomian gland dysfunction is characterizedby obstruction of a meibomian gland. In certain embodiments, the topicaladministration of the agent to the eyelid margin of the patient isrepeated until the meibomian gland obstruction is substantially removed.In certain embodiments, the topical administration of the agent to theeyelid margin of the patient is periodically repeated to preventformation of a meibomian gland obstruction.

In certain embodiments, the methods described above result in atherapeutically effective increase in the quantity of lipids produced bythe meibomian gland. In certain embodiments, the methods described aboveresult in a therapeutically effective increase in the quantity of lipidssecreted from the meibomian gland. In certain embodiments, the methodsdescribed above result in an alternation of the composition of lipidssecreted by meibomian gland. In certain embodiments, the methodsdescribed above result in an alternation, preferably reduction, of theviscosity of lipids secreted by meibomian gland.

In some embodiments, the active agents are formulated and applied suchthat they are acceptable to the surface of the eye (i.e. not causingundue irritation or disruption to the epithelial surface of the eye),and do not compromise lipid producing cells in contact with thecomposition.

In some embodiments, the composition is applied for a duration andfrequency that is acceptable and practical to the physician or patientadministering the agent. For example, a physician applies a compositiondescribed herein weekly or twice a week for several weeks to induceincrease in the quantity of lipids secreted from the meibomian gland andthe patient applies a different composition on a daily basis, or thepatient uses a more potent composition on a daily basis for severalweeks and then, subsequently uses a less potent composition of a dailybasis thereafter. In some embodiments, the composition is applied by thepatient on a daily basis once or several times a day.

In some embodiments, the method of application varies, depending on theconcentration of the agent and/or the extent of lipid deficiency. Inother embodiments, the method of application of the composition istailored to enhance the penetration or residency time on the targettissue in order to enhance the effect of the treatment. In otherembodiments, the method of application of the composition is varied toenhance the penetration or residency time on the target tissue tominimize the amount of application time necessary. In other embodiments,the composition is formulated (e.g., by adjusting viscosity and/orskin-adhesiveness) to increase contact with the target tissue whileminimizing contact with non-target tissues, including the eye, and thuslimit or reduce any undesired collateral activity.

In certain embodiments, the concentration of the agent and of theexcipients is optimized to deliver the minimum effective concentrationof the agent to achieve the therapeutic benefit while minimizing anyocular irritation or disruption, or irritation or disruption tosurrounding ocular tissues.

The methods and compositions described herein are means for increasingthe quantity of lipids secreted from meibomian glands, altering thecomposition of the lipids secreted by the meibomian glands, and/orreducing the viscosity of lipids secreted from meibomian glands, therebyenhancing the dissolution of any meibomian gland obstruction andimproving tear breakup time (TBUT).

The compositions used in the methods of the present invention include atleast one lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing agent. In some embodiments, theagent is a thiol-containing, —SeH containing, drug that causes increasedmeibum production. In some embodiments, the agent is a thiol-containing,—SeH containing, drug such as Captopril, Zofenopril, Tiopronin,Penicillamine, L-Cysteine, Selenocysteine, Gluthatione, Dithiothreitol,Thiorphan, Cysteamine, Bucillamine, Dimercaprol, 1,1-Ethanedithiol,Dimercaptosuccinic acid, Furan-2-ylmethanethiol, Omapatrilat, OvothiolA, Pantetheine, Rentiapril, Thiosalicylic acid, Tixocortol, Mycothiol,Coenzyme A, Coenzyme B. Their chemical structures are presented in Table2.

TABLE 2 Chemical structures of certain thiol-containing, or —SeHcontaining drugs. Captopril

Zofenopril

Tiopronin

Penicillamine

Selenocysteine

L-cysteine

Gluthatione

Dithiothreitol

Thiorphan

Cysteamine

Bucillamine

Dimercaprol

1,1-Ethanedithiol

Dimercaptosuccinic acid

Furan-2-ylmethanethiol

Omapatrilat

Ovothiol A

Pantetheine

Rentiapril

Thiosalicylic acid

Tixocortol

Mycothiol

Coenzyme A

Coenzyme B

Gemopatrilat

Sulfanegen

Selenium D-methionine

In some embodiments, the agent is a disulfide containing drug such asdisulfiram, Psammaplin A, Dixanthogen, Pantethine, Fursultiamine,Octotiamine, Sulbutiamine, Prosultiamine, Thiram, Lipoic acid,Lenthionine, Ajoene, Allicin, Gemopatrilat, and Sulfanegen. Theirchemical structures are presented in Table 3.

TABLE 3 Chemical structures of disulfide containing drugs. Disulfiram

Psammaplin A

Dixanthogen

Pantethine

Fursultiamine

Octotiamine

Sulbutiamine

Prosultiamine

Thiram

Lipoic acid

Lenthionine

Ajoene

Allicin

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isCaptopril.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isZofenopril.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isTiopronin.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isPenicillamine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isL-Cysteine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isSelenocysteine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isGluthatione.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isDithiothreitol.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isThiorphan.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isCysteamine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isBucillamine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isDimercaprol.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent is1,1-Ethanedithiol.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isDimercaptosuccinic acid.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isFuran-2-ylmethanethiol.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isOmapatrilat.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isOvothiol A.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isPantetheine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isRentiapril.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isThiosalicylic acid.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isTixocortol.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isMycothiol.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isCoenzyme A.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isCoenzyme B.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isGemopatrilat.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isSulfanegen.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isSelenium D-methionine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isdisulfiram.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isPsammaplin A.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isDixanthogen.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isPantethine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isFursultiamine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isOctotiamine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isSulbutiamine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isProsultiamine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isThiram.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isLipoic acid.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isLenthionine.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isAjoene.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isAllicin.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isGemopatrilat.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isSulfanegen.

The present invention provides, for the first time, derivatives oflipids containing sulfhydryl groups and/or disulfides, useful forenhancing the secretion of the meibum lipids in-vivo, and in treatingmeibomian gland dysfunction (MGD).

More specifically, also described herein are methods for enhancinglipogenesis in meibomian glands, for lowering the melting point oflipids secreted from meibomian glands, for reducing the viscosity oflipids secreted from meibomian glands, and for reducing the viscosity oflipids in the eyelid margins, by administering thiol-containing ordisulfide-containing lipid derivatives. The lipid derivatives describedherein include lipid derivatives for acute therapies, for use, e.g., bya physician or other trained specialist, and lipid derivatives forchronic therapies, e.g., either by a physician or other trainedspecialist, or by the patient. Certain lipid derivatives are describedherein; further provided herein are methods for preparing lipidderivatives as well as their use in methods of treatment of patients.

According to the principles of the present invention, thiol-containingor disulfide-containing lipid derivatives which induce lipogenesis andmeibum lipid secretion, can be used, e.g., as treatment for MGD throughthiol-mediated lipid over-secretion mechanisms. More according to theprinciples of the present invention, disulfide containing lipidderivatives, present thiol or sulfhydryl radicals once the disulfidebond is cleaved within the body by enzymes or chemical reactions.

Lipid derivatives-induced activation of cellular lipogenesis thusrepresents a new approach for therapeutic treatment of MGD throughenhanced synthesis of cholesterol and increased production of fattyacids and triglycerides that lead to alterations in composition of themeibum lipids, by decreasing the melting point and viscosity of themeibum lipids, which results in a more fluid appearance of meibumlipids.

The lipogenesis and lipid secretion enhancing lipid derivativesdescribed herein are useful either as an acute therapy (e.g., by atrained specialist or physician) or as a chronic therapy (e.g., in thehands of a patient, or alternatively, by a trained specialist orphysician). The agents are tested, in certain embodiments, using theassays and methods described herein (e.g., as described in theexamples).

The present invention provides, in one aspect, a method for increasinglipid secretion from a meibomian gland, comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition comprising an ophthalmically-acceptable carrierand an effective amount of at least one lipid-derivative comprising asulfhydryl group or a disulfide.

The present invention further provides, in another aspect, a method fortreating MGD, comprising topically administering to the eyelid margin ofthe patient in need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and a therapeutically-effective amountof at least one lipid-derivative comprising a sulfhydryl group or adisulfide.

The present invention further provides, in another aspect, a method forincreasing lipid production in a meibomian gland, comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition comprising an ophthalmically-acceptable carrierand an effective amount of at least one lipid-derivative comprising asulfhydryl group or a disulfide.

The present invention further provides, in another aspect, a method forlowering the melting point of lipids secreted from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone lipid-derivative comprising a sulfhydryl group or a disulfide.

The present invention further provides, in another aspect, a method forreducing the viscosity of lipids secreted from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone lipid-derivative comprising a sulfhydryl group or a disulfide.

The present invention further provides, in another aspect, a method forreducing the viscosity of lipids in an eyelid margin, comprisingtopically administering to the eyelid margin of the patient in needthereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone lipid-derivative comprising a sulfhydryl group or a disulfide.

In certain embodiments, the lipid-derivative is a derivative of a lipidselected from the group consisting of a fatty acid, a glycerolipid, aglycerophospholipid, a sphingolipid, a sterol lipid, a prenol lipid, asaccharolipid, a polyketide, and any combination thereof. Eachpossibility represents a separate embodiment of the invention. Incertain embodiments, the lipid-derivative is a derivative of a lipidfound naturally in the meibum.

In some embodiments, the lipid derivative is a lipid containing a —S—Hor disulfide such as Thiophospholipid, Thiocholesterol,12-Mercaptododecanoic acid or23-(9-Mercaptononyl)-3,6,9,12,15,18,21-Heptaoxatricosanoic Acid.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isThiophospholipid.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isThiocholesterol.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent is12-Mercaptododecanoic acid.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent is23-(9-Mercaptononyl)-3,6,9,12,15,18,21-Heptaoxatricosanoic Acid.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isThioethanol.

A method for increasing lipid secretion from a meibomian gland,comprising topically administering to the eyelid margin of the patientin need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isselenium disulfide.

In certain embodiments, the lipid is selected from the group consistingof a fatty acid, a wax ester, a cholesterol ester, a tri-glyceride, adi-glyceride, a mono-glyceride, a phospholipid, a diester, a fatty acidamide, squalene, a ceramide, a sphingolipid, a co-hydroxy fatty acid,cholesterol, and epoxides thereof. Each possibility represents aseparate embodiment of the invention.

In certain embodiments, the fatty acid has a molecular formula selectedfrom the group consisting of: (i) C_(n)H_(2n)O₂, wherein n is anyinteger selected from 12, 14-18 and 20-29; (ii) C_(n)H_(2n-2)O₂, whereinn is any integer selected from 16-18, 20, 22, 24, 26, 28, 30 and 32; and(iii) C_(n)H_(2n-4)O₂, wherein n is 18. In certain embodiments, thefatty acid is selected from the group consisting of myristic acid,palmitic acid, stearic acid, and oleic acid. Each possibility representsa separate embodiment of the invention.

In certain embodiments, the wax ester is an oleic acid ester of asaturated C₁₈₋₃₀ fatty acid. In certain embodiments, the cholesterolester is a cholesterol ester of a C₁₆₋₃₄ fatty acid. Each possibilityrepresents a separate embodiment of the invention.

In certain embodiments, the triglyceride has a molecular formulaselected from the group consisting of: (i) C_(n)H_(2n-8)O₆, wherein n isany integer selected from 55 and 57; (ii) C_(n)H_(2n-10)O₆, wherein n isany integer selected from 55 and 57; and (iii) fatty acids chainsassociated with the triglycerides: C14:0, C15:0, C16:0, C16:1, C17:0,C18:0, C18:1, C18:2.9. Each possibility represents a separate embodimentof the invention.

In certain embodiments, the phospholipid is selected from the groupconsisting of phosphatidylcholine (PC), phosphatidylethanolamine (PE),alkylacylphosphatidylcholine, sphingomyelin, dihydrosphingomyelin,dimethylphosphatidylethanolamine, diphosphatidylglycerol (cardiolipin),ethanolamine plasmalogen, lysoethanolamine plasmalogen,lysophosphatidylcholine, lysophosphatidylethanolamine,lysophosphatidylserine, phosphatidic acid, phosphatidylglycerol,phosphatidylinositol, and phosphatidylserine. Each possibilityrepresents a separate embodiment of the invention.

In certain embodiments, the fatty acid amide is selected from the groupconsisting of oleamide, myristamide, palmitamide, stearamide, anderucamide. Each possibility represents a separate embodiment of theinvention.

In certain embodiments, the w-hydroxy fatty acid has a molecular formulaselected from the group consisting of: (i) C_(n)H_(2n-7)O₄, wherein n isany integer selected from 46-52; (ii) C_(n)H_(2n-4)O₄, wherein n is anyinteger selected from 42-50; (iii) C_(n)H_(2n-6)O₄, wherein n is anyinteger selected from 42, 44, 46, and 48-52; (iv) C_(n)H_(2n-8)O₄,wherein n is any integer selected from 48, 50, and 52; and (v)C_(n)H_(2n-10)O₄, wherein n is any integer selected from 50 and 52. Eachpossibility represents a separate embodiment of the invention.

In certain embodiments, the lipid-derivative is polar. In certainembodiments, the lipid-derivative is non-polar. In certain embodiments,the lipid-derivative comprises sulfhydryl group. In certain embodiments,the lipid-derivative comprises a disulfide.

In certain embodiments, the methods described above further comprise thestep of administering to the patient a keratolytic agent. In certainembodiments, the keratolytic agent is selected from the group consistingbenzoyl peroxide, coal tar, dithranol, salicylic acid, seleniumdisulfide, alpha-hydroxy acid, urea, boric acid, retinoic acid, lacticacid, sodium thioglycolate or allantoin. Each possibility represents aseparate embodiment of the invention.

In certain embodiments, the meibomian gland dysfunction is characterizedby obstruction of a meibomian gland. In certain embodiments, the topicaladministration of the lipid-derivative to the eyelid margin of thepatient is repeated until the meibomian gland obstruction issubstantially removed. In certain embodiments, the topicaladministration of the lipid-derivative to the eyelid margin of thepatient is periodically repeated to prevent formation of a meibomiangland obstruction.

One embodiment provides a method for increasing lipid secretion from ameibomian gland, comprising topically administering to the eyelid marginof the patient in need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone lipid-derivative comprising a sulfhydryl group or a disulfide.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland, wherein the lipid-derivative is a derivative ofa lipid selected from the group consisting of a fatty acid, aglycerolipid, a glycerophospholipid, a sphingolipid, a sterol lipid, aprenol lipid, a saccharolipid, a polyketide, and any combinationthereof.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland, wherein the lipid-derivative is a derivative ofa lipid found naturally in the meibum.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland, wherein the lipid is selected from the groupconsisting of a fatty acid, a wax ester, a cholesterol ester, atri-glyceride, a di-glyceride, a mono-glyceride, a phospholipid, adiester, a fatty acid amide, squalene, a ceramide, a sphingolipid, aw-hydroxy fatty acid, cholesterol, and epoxides thereof.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland wherein the lipid is a fatty acid and the fattyacid has a molecular formula selected from the group consisting of: (i)C_(n)H_(2n)O₂, wherein n is any integer selected from 12, 14-18 and20-29; (ii) C_(n)H_(2n-2)O₂, wherein n is any integer selected from16-18, 20, 22, 24, 26, 28, 30 and 32; and (iii) C_(n)H_(2n-4)O₂, whereinn is 18.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland wherein the lipid is a fatty acid and the fattyacid is selected from the group consisting of myristic acid, palmiticacid, stearic acid, and oleic acid.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland wherein the lipid is a wax ester and the waxester is an oleic acid ester of a saturated C₁₈-30 fatty acid.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland wherein the lipid is a cholesterol ester and thecholesterol ester is a cholesterol ester of a C₁₆-34 fatty acid.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland wherein the lipid is a triglyceride and thetriglyceride has a molecular formula selected from the group consistingof: (i) C_(n)H_(2n-8)O₆, wherein n is any integer selected from 55 and57; (ii) C_(n)H_(2n-10)O₆, wherein n is any integer selected from 55 and57; and (iii) fatty acids chains associated with the triglycerides:C14:0, C15:0, C16:0, C16:1, C17:0, C18:0, C18:1, C18:2.9.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland wherein the lipid is a phospholipid and thephospholipid is selected from the group consisting ofphosphatidylcholine (PC), phosphatidylethanolamine (PE),alkylacylphosphatidylcholine, sphingomyelin, dihydrosphingomyelin,dimethylphosphatidylethanolamine, diphosphatidylglycerol (cardiolipin),ethanolamine plasmalogen, lysoethanolamine plasmalogen,lysophosphatidylcholine, lysophosphatidylethanolamine,lysophosphatidylserine, phosphatidic acid, phosphatidylglycerol,phosphatidylinositol, and phosphatidylserine.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland wherein the lipid is a fatty acid amide and thefatty acid amide is selected from the group consisting of oleamide,myristamide, palmitamide, stearamide, erucamide and ceramide.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland wherein the lipid is a w-hydroxy fatty acid andthe w-hydroxy fatty acid has a molecular formula selected from the groupconsisting of: (i) C_(n)H_(2n-7)O₄, wherein n is any integer selectedfrom 46-52; (ii) C_(n)H_(2n-4)O₄, wherein n is any integer selected from42-50; (iii) C_(n)H_(2n-6)O₄, wherein n is any integer selected from 42,44, 46, and 48-52; (iv) C_(n)H_(2n-8)O₄, wherein n is any integerselected from 48, 50, and 52; and (v) C_(n)H_(2n-10)O₄, wherein n is anyinteger selected from 50 and 52.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland wherein the lipid-derivative is polar. Anotherembodiment provides the method wherein the lipid-derivative isnon-polar. Another embodiment provides the method wherein thelipid-derivative comprises sulfhydryl group. Another embodiment providesthe method wherein the lipid-derivative comprises a disulfide.

Another embodiment provides the method for increasing lipid secretionfrom a meibomian gland wherein the ophthalmically-acceptable carriercomprises at least one ophthalmically-acceptable excipient.

One embodiment provides a method for increasing lipid secretion from ameibomian gland, comprising topically administering to the eyelid marginof the patient in need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone lipid-derivative comprising a sulfhydryl group or a disulfide,wherein the method further comprises the step of administering to thepatient a keratolytic agent. Another embodiment provides the methodwherein the keratolytic agent is selected from the group consisting ofselenium sulfide, dithranol, benzoyl peroxide, urea, salicilyc acid,boric acid, lactic acid, retinoic acid, and an alpha-hydroxy acid.

One embodiment provides a method for treating meibomian glanddysfunction (MGD), comprising topically administering to the eyelidmargin of the patient in need thereof an ophthalmic compositioncomprising an ophthalmically-acceptable carrier and atherapeutically-effective amount of at least one lipid-derivativecomprising a sulfhydryl group or a disulfide.

Another embodiment provides the method for treating meibomian glanddysfunction (MGD), wherein the lipid-derivative is a derivative of alipid selected from the group consisting of a fatty acid, aglycerolipid, a glycerophospholipid, a sphingolipid, a sterol lipid, aprenol lipid, a saccharolipid, a polyketide, and any combinationthereof.

Another embodiment provides the method for treating meibomian glanddysfunction (MGD), wherein the lipid-derivative is a derivative of alipid found naturally in the meibum.

One embodiment provides a method for treating meibomian glanddysfunction (MGD), comprising topically administering to the eyelidmargin of the patient in need thereof an ophthalmic compositioncomprising an ophthalmically-acceptable carrier and atherapeutically-effective amount of at least one lipid-derivativecomprising a sulfhydryl group or a disulfide, wherein the method furthercomprises the step of administering to the patient a keratolytic agent.One embodiment provides a method for treating meibomian glanddysfunction (MGD) wherein the keratolytic agent is selected from thegroup consisting of selenium sulfide, dithranol, benzoyl peroxide, urea,salicylic acid, boric acid, lactic acid, retinoic acid, and analpha-hydroxy acid. Another embodiment provides the method for treatingmeibomian gland dysfunction (MGD) wherein the meibomian glanddysfunction is characterized by obstruction of a meibomian gland.Another embodiment provides the method for treating meibomian glanddysfunction (MGD) wherein the topical administration of thelipid-derivative to the eyelid margin of the patient is repeated untilthe meibomian gland obstruction is substantially removed. Anotherembodiment provides the method for treating meibomian gland dysfunction(MGD) wherein the topical administration of the lipid-derivative to theeyelid margin of the patient is periodically repeated to preventformation of a meibomian gland obstruction. Another embodiment providesthe method for treating meibomian gland dysfunction (MGD) wherein theophthalmically-acceptable carrier comprises at least oneophthalmically-acceptable excipient.

In certain embodiments, the methods described above result in asignificant, preferably statistically significant increase in thequantity of lipids produced by the meibomian gland. In certainembodiments, the methods described above result in a significant,preferably statistically significant increase in the quantity of lipidssecreted from the meibomian gland. In certain embodiments, the methodsdescribed above result in a significant, preferably statisticallysignificant alternation of the composition of lipids secreted by themeibomian gland. In certain embodiments, the methods described aboveresult in a significant, preferably statistically significantalternation, preferably reduction, of the melting point of lipidssecreted from the meibomian gland. In certain embodiments, the methodsdescribed above result in a significant, preferably statisticallysignificant alternation, preferably reduction, of the viscosity oflipids secreted by the meibomian gland. In certain embodiments, themethods described above result in a significant, preferablystatistically significant alternation, preferably reduction, of theviscosity of lipids in the eyelid margin.

In certain embodiments, the methods described above result in atherapeutically effective increase in the quantity of lipids produced bythe meibomian gland. In certain embodiments, the methods described aboveresult in a therapeutically effective increase in the quantity of lipidssecreted from the meibomian gland. In certain embodiments, the methodsdescribed above result in a therapeutically effective alternation of thecomposition of lipids secreted by the meibomian gland. In certainembodiments, the methods described above result in a therapeuticallyeffective alternation, preferably reduction, of the melting point oflipids secreted from the meibomian gland. In certain embodiments, themethods described above result in a therapeutically effectivealternation, preferably reduction, of the viscosity of lipids secretedby the meibomian gland. In certain embodiments, the methods describedabove result in a therapeutically effective alternation, preferablyreduction, of the viscosity of lipids in the eyelid margin.

In some embodiments, the active agents are formulated and applied suchthat they are acceptable to the surface of the eye (i.e. not causingundue irritation or disruption to the epithelial surface of the eye),and do not compromise lipid producing cells in contact with thecomposition.

In some embodiments, the composition is applied for a duration andfrequency that is acceptable and practical to the physician or patientadministering the agent. For example, a physician applies a compositiondescribed herein weekly or twice a week for several weeks to induceincrease in the quantity of lipids secreted from the meibomian gland andthe patient applies a different composition on a daily basis, or thepatient uses a more potent composition on a daily basis for severalweeks and then, subsequently uses a less potent composition of a dailybasis thereafter. In some embodiments, the composition is applied by thepatient on a daily basis once or several times a day.

In some embodiments, the method of application varies, depending on theconcentration of the lipid-derivative and/or the extent of lipiddeficiency. In other embodiments, the method of application of thecomposition is tailored to enhance the penetration or residency time onthe target tissue in order to enhance the effect of the treatment. Inother embodiments, the method of application of the composition isvaried to enhance the penetration or residency time on the target tissueto minimize the amount of application time necessary. In otherembodiments, the composition is formulated (e.g., by adjusting viscosityand/or skin-adhesiveness) to increase contact with the target tissuewhile minimizing contact with non-target tissues, including the eye, andthus limit or reduce any undesired collateral activity.

In certain embodiments, the concentration of the lipid-derivative and ofthe excipients is optimized to deliver the minimum effectiveconcentration of the lipid-derivative to achieve the therapeutic benefitwhile minimizing any ocular irritation or disruption, or irritation ordisruption to surrounding ocular tissues.

The methods and compositions described herein are means for increasingthe quantity of lipids secreted from meibomian glands, altering thecomposition of the lipids secreted by the meibomian glands, and/orreducing the viscosity of lipids secreted from meibomian glands, therebyenhancing the dissolution of any meibomian gland obstruction andimproving tear breakup time (TBUT).

In some embodiments, topical administration of at least onelipid-derivative twice a week. In some embodiments, topicaladministration of at least one lipid-derivative occurs every other day.In some embodiments, topical administration of at least onelipid-derivative occurs every day. In some embodiments, topicaladministration of at least one lipid-derivative occurs several times aday.

In some embodiments, the composition for topical administration is aliquid or a semi-solid. In some embodiments, the composition for topicaladministration is a semi-solid emulsion. In some embodiments, thecomposition for topical administration is a cream. In some embodiments,the composition for topical administration is an ointment. In someembodiments, the lipid-derivative is suspended or dispersed within thecomposition. In some embodiments, the composition for topicaladministration is a lotion. In some embodiments, the composition fortopical administration is a gel.

One embodiment provides a method for treating MGD in a patient in needthereof by topical administration of a composition comprising at leastone lipid-derivative, wherein the treatment results in atherapeutically-relevant increase in the quantity of lipids produced bythe meibomian gland. One embodiment provides a method for treating MGDin a patient in need thereof by topical administration of a compositioncomprising at least one lipid-derivative, wherein the treatment resultsin a therapeutically-relevant increase in the quantity of lipidssecreted from the meibomian gland. Another embodiment provides a methodfor treating MGD in a patient in need thereof by topical administrationof a composition comprising a lipid-derivative, wherein the treatmentresults in a therapeutically-relevant increase of meibum production.Another embodiment provides a method for treating MGD in a patient inneed thereof by topical administration of a composition comprisinglipid-derivative, wherein the treatment results in atherapeutically-relevant change in the meibum lipids' composition.Another embodiment provides a method for treating MGD in a patient inneed thereof by topical administration of a composition comprisinglipid-derivative, wherein the treatment results in atherapeutically-relevant decrease in the melting point of lipidssecreted from the meibomian gland. Another embodiment provides a methodfor treating MGD in a patient in need thereof by topical administrationof a composition comprising lipid-derivative, wherein the treatmentresults in a therapeutically-relevant decrease in the viscosity oflipids secreted from the meibomian gland. Another embodiment provides amethod for treating MGD in a patient in need thereof by topicaladministration of a composition comprising lipid-derivative, wherein thetreatment results in a therapeutically-relevant decrease in theviscosity of lipids in the eyelid margin.

In any of the aforementioned embodiments, the composition furthercomprises an ophthalmically-acceptable carrier. In one furtherembodiment, the ophthalmically-acceptable carrier comprises anophthalmically-acceptable excipient. In certain embodiments, theophthalmically-acceptable carrier comprises a plurality ofophthalmically-acceptable excipients. Such excipients are described, forexample, in Remington: The Science and Practice of Pharmacy (Gennaro,21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

One embodiment provides a method for enhancing lipogenesis and lipidsecretion from a meibomian gland in a patient in need thereof byadministering a topical composition comprising a lipid-derivative,wherein the composition comprises 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%,0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%,1.9%, 2.0%, 2.5%, 5%, or 10% of the lipid-derivative. In someembodiments, the composition is formulated as a suspension, emulsion,cream, lotion, gel, or ointment. In some embodiments, the composition isapplied as a thin layer to clean skin initially once daily on alternatedays, and is then gradually increased up to twice daily as tolerancedevelops. In some embodiments, the composition is an ointment or paste.In some embodiments, the composition is started as a 0.1% ointment.After 7 days, the concentration may be increased to 0.25% andsubsequently doubled, if necessary, at weekly intervals to a maximumstrength of 2%. In some embodiments, a thin layer of ointment is appliedonce daily to the affected areas for 2-4 weeks. In some embodiments, theointment is left in place for 10 to 20 minutes before the area is rinsedthoroughly. In some embodiments, the concentration of lipogenesis andlipid secretion enhancing thiol-containing or disulfide-containing drugor pharmaceutical agent is gradually increased to a maximum of 5%, andtreatment is continued for as long as necessary.

In some embodiments, the topical administration of the compositioncomprising a lipid-derivative occurs once a week. In some embodiments,the topical administration of the composition comprising alipid-derivative occurs twice a week. In some embodiments, the topicaladministration of the composition comprising a lipid-derivative occursevery other day. In some embodiments, the topical administration of thecomposition comprising a lipid-derivative occurs every day. In someembodiments, the topical administration of the composition comprising alipid-derivative occurs several times a day.

In some embodiment, the method comprises treatment in an acute treatmentscenario. In another embodiment, the method comprises treatment of apatient naïve to similar or identical treatment. In another embodiment,the method comprises treatment in a chronic treatment scenario. Inanother embodiment, the method comprises treatment in a maintenancetherapy scenario. In an acute treatment scenario, the administereddosage of lipid-derivatives may be higher than the administered dosageof lipid-derivatives employed in a chronic treatment scenario or amaintenance therapy scenario. In an acute treatment scenario, thelipid-derivatives may be different from the lipid-derivatives employedin a chronic treatment scenario. In some embodiments, the course oftherapy begins in the initial phase of therapy as an acute treatmentscenario and later transitions into a chronic treatment scenario or amaintenance therapy scenario.

In some embodiments, the agent is the active agent responsible forincreasing the quantity of lipids secreted from meibomian gland,altering the composition of the lipids secreted by the meibomian gland,and/or reducing the viscosity of the lipids secreted by the meibomiangland, thereby enhancing the dissolution of any meibomian glandobstruction.

In some embodiments, topical administration of at least one agent occurstwice a week. In some embodiments, topical administration of at leastone agent occurs every other day. In some embodiments, topicaladministration of at least one agent occurs every day. In someembodiments, topical administration of at least one agent occurs severaltimes a day.

In some embodiments, the composition for topical administration is aliquid or a semi-solid. In some embodiments, the composition for topicaladministration is a semi-solid emulsion. In some embodiments, thecomposition for topical administration is a cream. In some embodiments,the composition for topical administration is an ointment. In someembodiments, the agent is suspended or dispersed within the composition.In some embodiments, the composition for topical administration is alotion. In some embodiments, the composition for topical administrationis a gel.

Pharmaceutical acceptable topical compositions are prepared containingthe lipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent. Thegels are mainly hydrophilic and optionally contain suspending agent,dispersing agent, solubilizing agent, emulsifying agent, thickeningagent, preservative, antioxidant at the desired acceptableconcentrations for ophthalmic preparations. The ophthalmic ointments areprimarily anhydrous and contain mineral oil and white petrolatum as thebase ingredients. The petrolatum base can be made more miscible withaqueous components by addition of lanolin. Exemplary lipogenesis andlipid secretion enhancing formulations described herein further containsuspending agents, emulsifying agents, solubilizing agents or thickeningagents.

Suspending agents: A suspending agent helps to reduce the sedimentationrate of particles in suspension. These are insoluble particles that aredispersed in a liquid vehicle. The suspending agent works by increasingthe viscosity of the liquid vehicle, and thereby slowing down settlingin accordance with Stokes Law. Most suspending agents perform twofunctions. Besides acting as a suspending agent they also impartsviscosity to the solution. Suspending agents form film around particleand decrease inter-particle attraction. Suspending agents also act asthickening agents. They increase in viscosity of the solution, which isnecessary to prevent sedimentation of the suspended particles and thusaggregation or caking of the particles. Example of suspending agents arecellulose derivatives (CMC, HPMC, HEC), carbomers (carbopol,polycarophil), gums, alginates, gelatin, or colloidal silicon dioxide.

Emulsifying agents: An emulsifying agent helps maintain the dispersionof finely divided liquid droplets in a liquid vehicle. Emulsions aremade of two or more immiscible liquids such as water and an oil, and canbe a liquid or a semisolid such as a cream or lotion. The emulsifyingagents can be of natural origin like the lecithins (phospholipids) orsynthetic such as ionic (SLS) or non-ionic surfactants (cremophors,polysorbates, poloxamers).

Solubilizing agents: A solubilizing agent is used to enhance thesolubility and increase the bioavailability of a sparingly soluble drug.Solubilizing agents can be water-miscible alcoholic solvents like(polyethyleneglycol, propyleneglycol, glycerol), complexing agents suchas the cyclodextrins or water-soluble synthetic polymers like povidone(PVP) or polyvinylalcohol (PVA).

Thickening agents: A thickening agent is added to increase the viscosityof the suspension. All the ingredients are mixed by mechanical shakingto get a stable an homogeneous dispersion/suspension/solution of theactive lipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent in theointment or gel with the aid of the suspending, solubilizing,emulsifying or thickening agents.

The pharmaceutical compositions described herein comprise from about0.2% to about 10% lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug orpharmaceutical agent. In some embodiments, the pharmaceuticalcompositions described herein comprise from about 0.2% to about 1.0%lipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent. Insome embodiments, the pharmaceutical compositions described hereincomprise from about 1.0% to about 3.0% lipogenesis and lipid secretionenhancing thiol-containing, —SeH containing, or disulfide-containingdrug or pharmaceutical agent. In some embodiments, the pharmaceuticalcompositions described herein comprise from about 3.0% to about 5.0%lipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent. Insome embodiments, the pharmaceutical compositions described hereincomprise from about 5.0% to about 10.0% lipogenesis and lipid secretionenhancing thiol-containing, —SeH containing, or disulfide-containingdrug or pharmaceutical agent. In some embodiments, the pharmaceuticalcompositions described herein comprise from about 1.0% lipogenesis andlipid secretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent. In some embodiments,the pharmaceutical compositions described herein comprise from about1.5% lipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent. Insome embodiments, the pharmaceutical compositions described hereincomprise from about 2.0% lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug orpharmaceutical agent. In some embodiments, the pharmaceuticalcompositions described herein comprise from about 2.5% lipogenesis andlipid secretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent. In some embodiments,the pharmaceutical compositions described herein comprise from about3.0% lipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent. Insome embodiments, the pharmaceutical compositions described hereincomprise from about 3.5% lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug orpharmaceutical agent. In some embodiments, the pharmaceuticalcompositions described herein comprise from about 4.0% lipogenesis andlipid secretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent. In some embodiments,the pharmaceutical compositions described herein comprise from about4.5% lipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent. Insome embodiments, the pharmaceutical compositions described hereincomprise from about 5.0% lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug orpharmaceutical agent.

One embodiment provides a method for treating meibomian glanddysfunction in a patient in need thereof by topical administration of acomposition comprising at least one lipogenesis and lipid secretionenhancing thiol-containing, —SeH containing, or disulfide-containingdrug or pharmaceutical agent, wherein the lipogenesis and lipidsecretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent results in atherapeutically-relevant increase in the quantity of lipids secretedfrom the meibomian gland. Another embodiment provides a method fortreating meibomian gland dysfunction in a patient in need thereof bytopical administration of a composition comprising a lipogenesis andlipid secretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent, wherein thelipogenesis and lipid secretion enhancing pharmaceutical agent is apharmaceutical composition comprising selenium sulfide. Anotherembodiment provides a method for treating meibomian gland dysfunction ina patient in need thereof by topical administration of a compositioncomprising a lipogenesis and lipid secretion enhancing pharmaceuticalagent, wherein the lipogenesis and lipid secretion enhancingpharmaceutical agent is a pharmaceutical composition comprising athiol-containing, —SeH containing, or disulfide-containing drug. Anotherembodiment provides a method for treating meibomian gland dysfunction ina patient in need thereof by topical administration of a compositioncomprising a lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing drug or pharmaceutical agent,wherein the lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing drug or pharmaceutical agentcauses increased meibum production. Another embodiment provides a methodfor treating meibomian gland dysfunction in a patient in need thereof bytopical administration of a composition comprising a lipogenesis andlipid secretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent, wherein thelipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent is aPemphigus causing agent. Another embodiment provides a method fortreating meibomian gland dysfunction in a patient in need thereof bytopical administration of a composition comprising a lipogenesis andlipid secretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent, wherein thelipogenesis and lipid secretion enhancing pharmaceutical agent iscapable of increasing the quantity of meibum lipids secreted from themeibomian gland and altering the meibum lipids composition, therebyallowing dissolution of meibomian gland obstruction. Another embodimentprovides a method for treating meibomian gland dysfunction in a patientin need thereof by topical administration of a composition comprising alipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent,wherein the lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing drug or pharmaceutical agent iscapable of increasing the quantity of meibum lipids secreted from themeibomian gland upon application to eyelid margins, by virtue of itscontact with the contents of the meibomian gland orifice.

One embodiment provides a method for treating meibomian glanddysfunction by topical administration of a composition comprising alipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent,wherein the lipogenesis and lipid secretion enhancing pharmaceuticalagent is a pharmaceutical composition wherein at least one agent iscapable of increasing the quantity of meibum lipids secreted from themeibomian gland. Another embodiment provides a method for treatingmeibomian gland dysfunction in a patient in need thereof by topicaladministration of a composition comprising a lipogenesis and lipidsecretion enhancing pharmaceutical agent, wherein the lipogenesis andlipid secretion enhancing pharmaceutical agent is a pharmaceuticalcomposition comprising selenium sulfide. Another embodiment provides amethod for treating meibomian gland dysfunction by topicaladministration of a composition comprising a lipogenesis and lipidsecretion enhancing pharmaceutical agent, wherein the lipogenesis andlipid secretion enhancing pharmaceutical agent is a pharmaceuticalcomposition wherein the at least one agent capable of increasing thequantity of meibum lipids secreted from the meibomian gland is athiol-containing, —SeH containing, or disulfide-containing drug. Anotherembodiment provides a method for treating meibomian gland dysfunction bytopical administration of a composition comprising a lipogenesis andlipid secretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent, wherein thelipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent is apharmaceutical composition wherein the at least one agent capable ofincreasing the quantity of meibum lipids secreted from the meibomiangland causes sebum over-production. Another embodiment provides a methodfor treating meibomian gland dysfunction by topical administration of acomposition comprising a lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug orpharmaceutical agent, wherein the lipogenesis and lipid secretionenhancing thiol-containing, —SeH containing, or disulfide-containingdrug or pharmaceutical agent is a pharmaceutical composition wherein theat least one agent capable of increasing the quantity of meibum lipidssecreted from the meibomian gland is a Pemphigus causing agent. Anotherembodiment provides a method for treating meibomian gland dysfunction bytopical administration of a composition comprising a lipogenesis andlipid secretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent, wherein thelipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent is apharmaceutical composition wherein the at least one agent capable ofincreasing the quantity of meibum lipids secreted from the meibomiangland lowers the melting point of meibum lipids, thereby reducing theviscosity of meibum lipids and allowing dissolution of any meibomiangland obstruction. Another embodiment provides a method for treatingmeibomian gland dysfunction by topical administration of a compositioncomprising a lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing drug or pharmaceutical agent,wherein the lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing drug or pharmaceutical agent isa pharmaceutical composition wherein at least one agent is capable ofincreasing the quantity of meibum lipids secreted from the meibomiangland upon application to eyelid margins, by virtue of its contact withthe contents of the meibomian gland orifice.

One embodiment provides a method for treating meibomian glanddysfunction by topical administration of a composition comprising alipogenesis and lipid secretion enhancing pharmaceutical agent, whereinthe lipogenesis and lipid secretion enhancing pharmaceutical agent is adrug containing a thiol or disulfide group. Another embodiment providesa method for treating meibomian gland dysfunction by topicaladministration of a composition comprising a lipogenesis and lipidsecretion enhancing pharmaceutical agent, wherein the thiol containingdrug is selected from the group consisting of Captopril, Zofenopril,Tiopronin, Penicillamine, L-Cysteine, Selenocysteine, Gluthatione,Dithiothreitol, Thiorphan, Cysteamine, Bucillamine, Dimercaprol,1,1-Ethanedithiol, Dimercaptosuccinic acid, Furan-2-ylmethanethiol,Omapatrilat, Ovothiol A, Pantetheine, Rentiapril, Thiosalicylic acid,Tixocortol, Mycothiol, Coenzyme A, and Coenzyme B.

Another embodiment provides a method for treating meibomian glanddysfunction by topical administration of a composition comprising alipogenesis and lipid secretion enhancing pharmaceutical agent, whereinthe disulfide containing drug is selected from the group consisting ofdisulfiram, Psammaplin A, Dixanthogen, Pantethine, Fursultiamine,Octotiamine, Sulbutiamine, Prosultiamine, Thiram, Lipoic acid,Lenthionine, Ajoene, Allicin, Gemopatrilat, and Sulfanegen.

In any of the aforementioned embodiments, the composition furthercomprises an ophthalmically-acceptable carrier. In one furtherembodiment, the ophthalmically-acceptable carrier comprises anophthalmically-acceptable excipient.

In certain embodiments, lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug orpharmaceutical agents used in the methods and compositions describedherein are optionally used in a maintenance therapy setting. In certainembodiments, lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing drug or pharmaceutical agentsused in a maintenance therapy setting include low concentrations of alipogenesis and lipid secretion enhancing pharmaceutical agent.

The term “maintenance therapy” or “maintenance dosing regime” refers toa treatment schedule for a subject or patient diagnosed with adisorder/disease, e.g., MGD, to enable them to maintain their health ina given state, e.g., remission.

In one embodiment, the lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, drug or pharmaceutical agent used inmaintenance therapy setting is selected from the group consisting ofCaptopril, Zofenopril, Tiopronin, Penicillamine, L-Cysteine,Selenocysteine, Gluthatione, Dithiothreitol, Thiorphan, Cysteamine,Bucillamine, Dimercaprol, 1,1-Ethanedithiol, Dimercaptosuccinic acid,Furan-2-ylmethanethiol, Omapatrilat, Ovothiol A, Pantetheine,Rentiapril, Thiosalicylic acid, Tixocortol, Mycothiol, Coenzyme A, andCoenzyme B.

In one embodiment, the lipogenesis and lipid secretion enhancingdisulfide-containing drug or pharmaceutical agent used in maintenancetherapy setting is selected from the group consisting of disulfiram,Psammaplin A, Dixanthogen, Pantethine, Fursultiamine, Octotiamine,Sulbutiamine, Prosultiamine, Thiram, Lipoic acid, Lenthionine, Ajoene,Allicin, Gemopatrilat, and Sulfanegen.

One embodiment provides a method for enhancing lipogenesis and lipidsecretion, from meibomian gland, in a patient in need thereof byadministering a topical composition comprising a lipogenesis and lipidsecretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent, wherein thecomposition comprises 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%,0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%,2.5%, 5%, or 10% of lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug orpharmaceutical agent. In some embodiments, the composition is formulatedas a suspension, emulsion, cream, lotion, gel, or ointment. In someembodiments, the composition is applied as a thin layer to clean skininitially once daily on alternate days, and is then gradually increasedup to twice daily as tolerance develops. In some embodiments, thecomposition is an ointment or paste. In some embodiments, thecomposition is started as a 0.1% ointment. After 7 days, theconcentration may be increased to 0.25% and subsequently doubled, ifnecessary, at weekly intervals to a maximum strength of 2%. In someembodiments, a thin layer of ointment is applied once daily to theaffected areas for 2-4 weeks. In some embodiments, the ointment is leftin place for 10 to 20 minutes before the area is rinsed thoroughly. Insome embodiments, the concentration of lipogenesis and lipid secretionenhancing thiol-containing, —SeH containing, or disulfide-containingdrug or pharmaceutical agent is gradually increased to a maximum of 5%,and treatment is continued for as long as necessary.

In other embodiments, the topical compositions described herein arecombined with a pharmaceutically suitable or acceptable carrier (e.g., apharmaceutically suitable (or acceptable) excipient, physiologicallysuitable (or acceptable) excipient, or physiologically suitable (oracceptable) carrier). Exemplary excipients are described, for example,in Remington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)).

One embodiment provides a method for treating meibomian glanddysfunction by administering a topical composition comprising alipogenesis and lipid secretion enhancing thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent. Oneembodiment provides a method for treating meibomian gland dysfunction byadministering a topical composition comprising a lipogenesis and lipidsecretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent combined with akeratolytic agent.

In some embodiments, the topical administration of the compositioncomprising a lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing drug or pharmaceutical agentoccurs once a week. In some embodiments, the topical administration ofthe composition comprising a lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug orpharmaceutical agent occurs twice a week. In some embodiments, thetopical administration of the composition comprising a lipogenesis andlipid secretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent occurs every otherday. In some embodiments, the topical administration of the compositioncomprising a lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing drug or pharmaceutical agentoccurs every day. In some embodiments, the topical administration of thecomposition comprising a lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug orpharmaceutical agent occurs several times a day.

In some embodiment, the method comprises treatment in an acute treatmentscenario. In another embodiment, the method comprises treatment of apatient naïve to similar or identical treatment. In another embodiment,the method comprises treatment in a chronic treatment scenario. Inanother embodiment, the method comprises treatment in a maintenancetherapy scenario. In an acute treatment scenario, the administereddosage of lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing drug or pharmaceutical agentmay be higher than the administered dosage of lipogenesis and lipidsecretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent employed in a chronictreatment scenario or a maintenance therapy scenario. In an acutetreatment scenario, the lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug orpharmaceutical agent may be different from the lipogenesis and lipidsecretion thiol-containing, —SeH containing, or disulfide-containingdrug or enhancing pharmaceutical agent employed in a chronic treatmentscenario. In some embodiments, the course of therapy begins in theinitial phase of therapy as an acute treatment scenario and latertransitions into a chronic treatment scenario or a maintenance therapyscenario.

In certain clinical presentations, patients may require an initialtreatment administered by a physician or healthcare professional, eitherby placing a more highly concentrated composition of one of thetherapeutic agents described herein. In the event the higherconcentration compositions are required, the application thereof mayrequire ocular shielding or other activity to minimize the impact ofirritation or disruption of the ocular surface or surrounding tissues.Following such a procedure, a patient may be given a differentcomposition of active agent to take home to apply periodically to thelid margin to maintain the patency of the meibomian gland. Suchapplication may occur twice daily, once a day, weekly or monthly,depending on the composition activity and the desired product profile ofthe therapy.

One aspect of the methods of treatment described herein is the locationof the topical administration of the composition. In one embodiment, thecomposition comprising a lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug orpharmaceutical agent is administered such that no irritation to eyeoccurs. In one embodiment, the composition comprising a lipogenesis andlipid secretion enhancing thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent is administered to theeye lid margin.

One additional embodiment of the methods of treatment described hereinis the use of a protective element provided to the eye to avoidirritation to the eye. Although the compositions described herein aregenerally non-irritating, in some embodiments (e.g., high concentrationof agent or when used on a sensitive eye) a protective element providesan additional layer of safety and comfort for the patient. In oneembodiment, the composition comprising a lipogenesis and lipid secretionenhancing thiol-containing, —SeH containing, or disulfide-containingdrug or pharmaceutical agent is administered while an eye shield isplaced on the eye to reduce contact of the agent with the cornea and/orconjunctiva such that reduced irritation to eye occurs. In someembodiments, the eye shield is a contact lens or an eye covering. Insome embodiments, the eye covering comprises a self-adhesive. In oneembodiment, the composition comprising a lipogenesis and lipid secretionenhancing thiol-containing, —SeH containing, or disulfide-containingdrug or pharmaceutical agent is administered while the lid is pulledaway from the globe to reduce contact of the agent with the corneaand/or conjunctiva such that reduced irritation to eye occurs.

As used herein, the singular forms “a,” “and,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “an agent” includes a plurality of such agents,and reference to “the cell” includes reference to one or more cells (orto a plurality of cells) and equivalents thereof known to those skilledin the art, and so forth. When ranges are used herein for physicalproperties, such as molecular weight, or chemical properties, such aschemical formulae, all combinations and sub-combinations of ranges andspecific embodiments therein are intended to be included. The term“about” when referring to a number or a numerical range means that thenumber or numerical range referred to is an approximation withinexperimental variability (or within statistical experimental error), andthus the number or numerical range may vary between 1% and 15% of thestated number or numerical range. The term “comprising” (and relatedterms such as “comprise” or “comprises” or “having” or “including”) isnot intended to exclude that in other certain embodiments, for example,an embodiment of any composition of matter, composition, method, orprocess, or the like, described herein, may “consist of” or “consistessentially of” the described features.

The term “ophthalmically-acceptable carrier” as used herein refers to acarrier that does not cause significant irritation to the eye of anorganism when applied in accordance with the teachings of the presentinvention and does not abrogate the pharmacological activity andproperties of an agent carried therewith.

Ophthalmically acceptable carriers are generally sterile, essentiallyfree of foreign particles, and generally have a pH in the range of 5-8.Preferably, the pH is as close to the pH of tear fluid (7.4) aspossible. Ophthalmically acceptable carriers are, for example, sterileisotonic solutions such as isotonic sodium chloride or boric acidsolutions. Such carriers are typically aqueous solutions contain sodiumchloride or boric acid. Also useful are phosphate buffered saline (PBS)solutions.

The term “effective amount” as used herein refers to the amount that isneeded to achieve a particular condition, such as increasing lipidsecretion from a meibomian gland, lowering the melting point of lipidssecreted from a meibomian gland or reducing the viscosity of lipidssecreted from a meibomian gland.

The term “therapeutically effective amount” as used herein refers to anamount of a therapeutically effective compound, or a pharmaceuticallyacceptable salt thereof, which is effective to treat, prevent, alleviateor ameliorate symptoms of a disease. The term “therapeutically effectivecompound” refers to a compound that is effective to treat, prevent,alleviate or ameliorate symptoms of a disease.

The term “sulfhydryl group” as used herein refers to the —SH functionalgroup.

The term “thiol group” as used herein refers to —C—SH or R—SH group,where R represents an alkane, alkene, or other carbon-containing groupof atoms.

The term “disulfide” as used herein refers to a linked pair of sulfuratoms.

The term “disulfide bond” as used herein refers to a covalent bond,usually derived by the coupling of two thiol groups, the overallconnectivity is therefore —S—S—. The linkage is also called an SS-bondor disulfide bridge.

The term “ophthalmically-acceptable excipient” as used herein refers toan excipient that does not cause significant irritation to the eye of anorganism when applied in accordance with the teachings of the presentinvention and does not abrogate the pharmacological activity andproperties of an agent carried therewith.

The term “keratolytic agent” as used herein refers to a compound whichloosens and removes the stratum corneum of the skin, or alters thestructure of the keratin layers of skin.

The terms “treat,” “treating,” or “treatment” as used herein, includereducing, alleviating, abating, ameliorating, relieving, or lesseningthe symptoms associated with MGD in either a chronic or acutetherapeutic scenario. In one embodiment, treatment includes an increasein lipid production. In one embodiment, treatment includes an increasein lipid secretion. In one embodiment, treatment includes a decrease inthe viscosity of the lipids secreted.

The term “recurrence,” or “reducing relapse” refers to return of MGDsymptoms in a chronic therapeutic scenario.

The term “opening” refers to the clearing (at least in part) of anobstructed meibomian gland canal or orifice and/or maintaining thepatency of the meibomian gland canal or orifice.

The term “lipogenesis and lipid secretion enhancing thiol-containing,—SeH containing, or disulfide-containing drug or pharmaceutical agent”as used herein refer to a thiol-containing, —SeH containing, ordisulfide-containing drug or pharmaceutical agent that causes increasesdifferentiation of meibocytes or increases proliferation of meibocytesor increases the quantity of lipids secreted from the meibomian glandsor alters the composition of meibum lipids.

The term “meibum lipids” as used herein refers to lipids secreted bymeibomian gland.

The term “lotion” describes an emulsion liquid dosage form. This dosageform is generally for external application to the skin (US FDA DrugNomenclature Monograph, number C-DRG-00201).

The term “cream” describes an emulsion semisolid dosage form, usuallycontaining >20% water and volatiles and/or <50% hydrocarbons, waxes orpolyols as the vehicle. A cream is more viscous than a lotion. Thisdosage form is generally for external application to the skin (US FDADrug Nomenclature Monograph, number C-DRG-00201).

The term “ointment” describes a semisolid dosage form, usuallycontaining <20% water and volatiles and/or >50% hydrocarbons, waxes orpolyols as the vehicle. This dosage form is generally for externalapplication to the skin or mucous membranes (US FDA Drug NomenclatureMonograph, number C-DRG-00201).

The term “solution” describes a clear, homogeneous liquid dosage formthat contains one or more chemical substances dissolved in a solvent ormixture of mutually miscible solvents (US FDA Drug NomenclatureMonograph, number C-DRG-00201).

The term “suspension” refers to a heterogeneous mixture containing solidparticles that are sufficiently large for sedimentation.

The term “lipid-derivative” as used herein generally refers tohydrophobic or amphiphilic molecules comprising at least one sulfhydrylgroup or at least one disulfide. The term “lipid-derivative” furtherrefers to hydrophobic or amphiphilic molecules comprising at least onesulfhydryl group and at least one disulfide. The term “lipid-derivative”further refers to combinations and mixtures of lipid-derivatives.

The thiol-containing and/or disulfide-containing lipids or“lipid-derivatives” described by the present invention are highlyheterogeneous in terms of structure and derivation levels. For examples,lipids, such as cholesterol, may have a plurality of differentthiol-containing derivatives (FIG. 4). Methods to synthesize fatty thiolcompounds were previously described (J. Org. Chem., 1958, Vol. 23, pages1525-1530), producing a plurality of lipids linked by a disulfide (FIG.5). Also previously described are methods for synthesizingdisulfide-containing lipids (FIG. 6), as well as methods forsynthesizing multiple-thiol-containing lipids, such as squalene (FIG.7). Mono-, di- and tri-glycerides were also converted to theirthiol-containing derivatives (FIG. 8). In summary, lipids may bederivative to produce a wide range of thiol-containing and/ordisulfide-containing derivatives by methods which are well known in theart.

EXAMPLES Example 1: In Vivo Evaluation of the Effect of Thiol orDisulfide Containing Compounds on Lipid Synthesis in a 3D Model Cultureof Sebocytes

Since secretory cells (meibocytes) of meibomian glands, sharesimilarities with that of the secretory cells (sebocytes) of sebaceousglands, as can be validated from their similar structure, similarfunction and their joint embryologic development (Knop 2011_IOVS) theeffect of Thiol containing Lipids on lipid production can be evaluatedin a 3D model culture of Sebocytes. See also: Barrault 2012,Immortalized sebocytes can spontaneously differentiate into asebaceous-like phenotype when cultured as a 3D epithelium, Exp. Derm,21:299-319

The effect of different compounds on lipid synthesis was evaluated, in a3D model culture of Sebocytes. Drug candidates were drugs containing S—Hor disulfide: Selenium disulfide (SeS2 dispersed inCarboxymethylCellulose—CMC) as a positive control, Selenocysteine,Captopril, Disulfiram and lipids containing S—H or disulfide:Thioethanol, 12-Mercaptododecanoic acid. Since Sebocytes differentiationis associated with increased lipid synthesis and accumulation,evaluation of proliferation and differentiation was done by quantifyinglipid accumulation in the 3D Sebocytes culture (human cellline—SEBO662). Lipid accumulation was evaluated by lipid staining withOil red staining.

Sebocytes SEBO662 were cultured into a three dimension (3D) epitheliumand differentiated to a sebaceous-like phenotype. The Sebocytes weretreated or not (control) with the test compounds and incubated for 14days. All experiments were performed 3 times. After incubation, tissueswere snap-frozen. Formaldehyde-fixed cryo sections were stained using anOil-red-O solution and counterstained using haematoxylin. For each testcondition, the sections were observed using a light microscope equippedwith a camera. Five pictures were taken per replicate, making 15 valuesper treatment condition. The lipid content in each sample was quantifiedby calculation of the lipid droplet surface area. Quantitativecomparison of all data points between lipid's droplet surface area oftested compounds versus control was performed

Results:

FIG. 1 is an illustration of Oil-red-0 staining in 3D Sebocytesepithelium for the control.

FIG. 2 is an illustration of Oil-red-0 staining in 3D Sebocytesepithelium for 1.0 micromolar 12-mercaptododecanoic acid.

FIG. 3 is an illustration of Oil-red-0 staining in 3D Sebocytesepithelium for 0.1 micromolar 12-mercaptododecanoic acid.

Quantitative Comparison

Selenium disulfide (SeS2), at 0.01 μM and 0.1 induced a statisticallysignificant increase of lipid accumulation, in the upper region of the3D Sebocytes, at both test concentrations (282% and 348% of the control,respectively).

Selenocysteine, tested at 1 μM and 10 μM. At concentration of 1 thecompound induced a statistically significant increase in lipidaccumulation in the 3D sebocytes (296% of the control). At 10 nostimulation effect was found.

Captopril, tested at 1.0 μM and 10 induced a statistically significantincrease of lipid accumulation, at both test concentrations (240% and173% of the control, respectively).

Disulfiram, tested at 100 μM and 1000 μM. At concentration of 100stimulated a statistically significant increase in lipid accumulation inthe 3D sebocytes (199% of the control). At 1000 no stimulation effectwas found.

Thioethanol, tested at 0.1 and 1 stimulated a statistically significantincrease of lipid accumulation, at both test concentrations (251% and228% of the control, respectively).

12-Mercaptododecanoic acid, tested at 0.1 μM and 1 induced astatistically significant increase of lipid accumulation in 3Dsebocytes. This effect was similar at both concentrations (385% and 349%compared to the control, respectively)

Conclusions:

Selenium disulfide, Selenocysteine, Thioethanol, Captopril, Disulfiram,and 12-Mercaptododecanoic acid, which are compounds that contain S—H ordisulfide, had a significant stimulating effect on lipid synthesis inthe 3D Sebocytes model.

Example 2: Preparation of a Pharmaceutical Composition Comprising aLipogenesis and Lipid Secretion Enhancing Thiol-Containing, —SeHContaining, or Disulfide-Containing Drug or Pharmaceutical Agent

-   -   2.5 grams of 12-Mercaptododecanoic acid is mixed with 10 grams        of liquid paraffin and 87.5 grams of white soft petrolatum and        heated to ˜60° C. with constant stirring until homogeneous        mixture is obtained and cooled to room temperature.    -   2.5 grams of 12-Mercaptododecanoic acid is mixed with 2.5 grams        of cholesterol, 10 grams of liquid petrolatum, and 85 grams of        Vaseline. The mixture is heated under mixing until all        ingredients melt ˜80° C. and homogeneity obtained and then        cooled to room temperature.    -   2.5 grams of 12-Mercaptododecanoic acid is mixed with 5 grams of        squalene and 97.5 grams of Vaseline and heated to ˜60° C. with        mixing in order to obtain homogeneity and then cooled to room        temperature    -   2.5 grams of 12-Mercaptododecanoic acid is mixed with 10 grams        of mineral oil, 10 grams of squalene, 10 grams of        capric/caprylic triglyceride, 10 grams of microcrystalline wax,        10 grams of hydrogenated vegetable oil, and 3 grams of lanoline        and Vaseline to 100 grams. The mixture is heated to ˜80°        C.-90° C. with mixture until homogeneity is obtained and cooled        to room temperature.    -   2.5 grams of thiocholeterol is mixed with 10 grams of mineral        oil, 10 grams of squalene, 10 grams of capric/caprylic        triglyceride, 10 grams of microcrystalline wax, 10 grams of        hydrogenated vegetable oil, and 3 grams of lanoline and Vaseline        to 100 grams. The mixture is heated to ˜80° C.-90° C. with        mixture until homogeneity is obtained and cooled to room        temperature.    -   2.5 grams of thiophospholipid is mixed with 10 grams of mineral        oil, 10 grams of squalene, 10 grams of capric/caprylic        triglyceride, 10 grams of microcrystalline wax, 10 grams of        hydrogenated vegetable oil, and 3 grams of lanoline and Vaseline        to 100 grams. The mixture is heated to ˜80° C.-90° C. with        mixture until homogeneity is obtained and cooled to room        temperature.    -   2.5 grams of        23-(9-Mercaptononyl)-3,6,9,12,15,18,21-Heptaoxatricosanoic Acid        is mixed with 10 grams of mineral oil, 10 grams of squalene, 10        grams of capric/caprylic triglyceride, 10 grams of        microcrystalline wax, 10 grams of hydrogenated vegetable oil,        and 3 grams of lanoline and Vaseline to 100 grams. The mixture        is heated to ˜80° C.-90° C. with mixture until homogeneity is        obtained and cooled to room temperature.    -   2.5 grams of disulfiram is mixed with 10 grams of mineral oil,        10 grams of squalene, 10 grams of capric/caprylic triglyceride,        10 grams of microcrystalline wax, 10 grams of hydrogenated        vegetable oil, and 3 grams of lanoline and Vaseline to 100        grams. The mixture is heated to ˜80° C.-90° C. with mixture        until homogeneity is obtained and cooled to room temperature.    -   2.5 grams of thiophospholipids is mixed with 3 grams of        cholesterol and 10 grams of phospholipids and dissolved in        ethanol acetone mixture. The mixture is dried under vacuum and        mixed with 1000 ml of saline solution under vigorous agitation        following high-pressure homogenization to produce very fine        liposome dispersion.    -   2.5 grams of disulfiram is mixed with 5 grams of hydrogenated        vegetable oil and 5 grams of mineral oil and heated to ˜80° C.        with stirring until all ingredients are melted. 87.5 grams of        pre heated water solution to 80° C. comprising 1% tween80 and 2%        phospholipids are added under vigorous mixing and high shear        homogenization. 0.8 grams of xanthan gum (Xantural 3000™) is        added under vigorous mixing and the mixture is cooled to room        temperature to obtain solid lipid dispersion.    -   2.5 grams of captopril is dissolved in sterile water for        injection, 1.2 grams of xanthan gum and 0.8 grams of sodium        chloride are added and the mixture is agitated to produce a        clear gel.

Example 3: Increasing Lipid Production in Meibomian Glands

The objective of the study is to evaluate the effect of a lipogenesisand lipid secretion enhancing formulations on increasing the quantity oflipids produced by the meibomian glands.

A light layer of lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug or agentis applied to the lower lid of a subject, and the quantity of lipidsproduced by the meibomian gland is measured before and after applicationof the drug or agent. An exemplary method to determine the level oflipid production in the meibomian gland is by culturing human meibomiangland epithelial cells with and without the thiol-containing, —SeHcontaining, or disulfide-containing drug or pharmaceutical agent for 1,3, 5 and 7 days and then determining the magnitude of cellular lipid andlysosome accumulation by staining cells with LipidTOX green neutrallipid stain and LysoTracker® Red DND-99 (a fluorescent techniquedesigned for labeling lysosomes). Additionally, by examining whether thethiol-containing, —SeH containing, or disulfide-containing drugincreases the synthesis of polar and neutral lipid species in humanmeibomian gland epithelial cells, by culturing cells in media with orwithout the thiol-containing, —SeH containing, or disulfide-containingdrug groups for 7 days and then processing the cells for theidentification of phospholipids, and wax and cholesterol esters. Theselatter 2 species are the predominant lipids in human meibum. Theanalyses involve the use of high-performance thin-layer chromatographyand the quantification of staining intensities with ImageJ dye. Anotherknown alternative method utilizes Oil red 0 and Nile red staining. Thedegree of lipid accumulation is determined through the use of Nile Reddye. This dye will give a fluorescent signal which is proportional tothe amount of lipids which have been accumulated.

Example 4: Increasing Lipid Secretion from Meibomian Glands

The objective of the study is to evaluate the effect of a lipogenesisand lipid secretion enhancing formulations on increasing the quantity oflipids secreted from the meibomian glands.

A light layer of lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug or agentis applied to the lower lid of a subject, and the quantity of lipidssecreted from the meibomian gland is measured before and afterapplication of the drug or agent. An exemplary method to determine thelevel of lipid secretion from the meibomian gland is using a“meibometer” instrument for quantifying meibomian lipid on the lidmargin, which is an optical spectrophotometer that has tapes that areput against the lid margin to measure the amount of meibum beingsecreted (Chew et al, Current Eye Research, Vol. 12 (3), pages 247-254,1993).

Example 5: Lowering the Melting Point of Lipids Secreted from MeibomianGlands

The objective of the study is to evaluate the effect of a lipogenesisand lipid secretion enhancing formulations on lowering the melting pointof lipids secreted from the meibomian glands.

A light layer of lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug or agentis applied to the lower lid of a subject, and the melting point oflipids secreted from the meibomian gland is measured before and afterapplication of the drug or agent. An exemplary method to determine themelting point of lipid secretion from the meibomian gland is weighing anamount of 100 milligrams meibum lipids and dissolving them inchloroform-methanol (3:1) solvent mixture. Small portions of the abovemixture are withdrawn and put onto a pre-weighed Differential Scanningcalorimeter (DSC) pan. Subsequently the solvent is evaporated under astream of nitrogen to get a uniformly mixed sample. The DSC pans areweighed again to determine the accurate weight of the lipids. Thesamples are then analyzed in triplicate using the DSC and run from −50°C. to 100° C. at the rate of 5° C./minute. Singular components are alsorun under similar conditions as reference to identify them in mixtures.The separate components are run as is, as well as after dissolving inchloroform-methanol mixtures and after the evaporation of solvents. Themelting points are recorded as peaks in the DSC thermograms.

Example 6: Reducing the Viscosity of Lipids Secreted from MeibomianGlands

The objective of the study is to evaluate the effect of a lipogenesisand lipid secretion enhancing formulations on reducing the viscosity oflipids secreted from the meibomian glands.

A light layer of lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug or agentis applied to the lower lid of a subject, and the viscosity of lipidssecreted from the meibomian gland is measured before and afterapplication of the drug or agent. An exemplary method to determine theviscosity of lipid secretion from the meibomian gland is by using theBrookfield Cone/Plate Viscometer of special geometry gives researchers asophisticated instrument for routinely determining absolute viscosity offluids in small sample volumes. The Brookfield Cone/Plate Viscometerprovides a wide variety of shear rates and viscosity ranges, which canbe further extended by the use of interchangeable cone spindles.Different models can be selected to meet the specific range ofviscosities and shear rates required. The small sample volume requiredpermits rheological evaluations to be made on materials where sampleavailability is limited, such as biological fluids and meibum samples.

Example 7: Treatment of MGD Patients

The objective of the study is to evaluate the effect of a lipogenesisand lipid secretion enhancing formulations on treating MGD or at leastone of its symptoms.

A light layer of lipogenesis and lipid secretion enhancingthiol-containing, —SeH containing, or disulfide-containing drug or agentis applied to the lower lid of an MGD patient, and the severity of MGDor at least one of its symptoms is measured before and after applicationof the drug or agent. Exemplary methods for assessing and monitoring theseverity of MGD or at least one of its symptoms include, but are notlimited to patient questionnaires, meibomian gland expression, tearstability break up time, and determining the number of patent glands asseen by digital expression. Other methods for assessing MGD symptoms,include but are not limited to, Shirmer test, ocular surface staining,lid morphology analysis, meibography, meibometry, interferometry,evaporimetry, tear lipid composition analysis, fluorophotometry,meiscometry, osmolarity analysis, indices of tear film dynamics,evaporation and tear turnover.

1-30. (canceled)
 31. A method for increasing lipid secretion from ameibomian gland, comprising topically administering to the eyelid marginof the patient in need thereof an ophthalmic composition comprising anophthalmically-acceptable carrier and an effective amount of at leastone agent which increases lipogenesis in the meibomian gland orincreases lipid secretion from the meibomian gland, wherein the agent isthiorphan or tixocortol.
 32. The method of claim 31, wherein theophthalmically-acceptable carrier comprises at least oneophthalmically-acceptable excipient.
 33. The method of claim 31, furthercomprising the step of administering to the patient a keratolytic agent.34. The method of claim 33, wherein the keratolytic agent is selectedfrom the group consisting of benzoyl peroxide, coal tar, dithranol,salicylic acid, selenium disulfide, alpha-hydroxy acid, urea, boricacid, retinoic acid, lactic acid, sodium thioglycolate or allantoin. 35.The method of claim 31, wherein the agent is thiorphan.
 36. The methodof claim 31, wherein the agent is tixocortol.
 37. A method forincreasing lipid secretion from a meibomian gland, comprising topicallyadministering to the eyelid margin of the patient in need thereof anophthalmic composition comprising an effective amount of a single agentwhich increases lipogenesis in the meibomian gland or increases lipidsecretion from the meibomian gland, wherein the agent is thiorphan ortixocortol.
 38. The method of claim 37, further comprising the step ofadministering to the patient a keratolytic agent.
 39. The method ofclaim 38, wherein the keratolytic agent is selected from the groupconsisting of benzoyl peroxide, coal tar, dithranol, salicylic acid,selenium disulfide, alpha-hydroxy acid, urea, boric acid, retinoic acid,lactic acid, sodium thioglycolate or allantoin.
 40. The method of claim37, wherein the agent is thiorphan.
 41. The method of claim 37, whereinthe agent is tixocortol.